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National Institute on Drug Abuse

Director's Report to the National Advisory Council on Drug Abuse

May, 1999

Research Findings

Behavioral Research

Phencyclidine- and Diazepam-Like Discriminative Stimulus Effects of Inhalants in Mice

It has been shown that abused solvents, such as 1,1,1-trichloroethane (TCE) and toluene, share certain pharmacological properties with central nervous system depressants, such as alcohol and anesthetic vapors. Several vapors were tested for diazepam (DZ)- and phencyclidine (PCP)-like discriminative stimulus effects to further explore their pharmacological specificity. In DZ-trained mice, methoxyflurane fully substituted, and TCE produced partially substituted for PCP. In a test for substitution of fluorothyl and toluene for DZ, neither produced appreciable DZ-lever responding at any concentration tested. On the other hand, toluene produced concentration- related partial substitution for PCP. Methoxyflurane, TCE, and fluorothyl produced no substitution for PCP. The substitution of some of these vapors for DZ or PCP suggests that, like ethanol, the discriminative stimulus effects of abused solvents partially overlap those of N-methyl-D- aspartate antagonists as well as those of gamma amino butyric acid agonists. Bowen, S.E., Wiley, J.L., Jones, H.E., and Balster, R.L. Exp. Clin. Psychopharmacology, pp. 28-37, 1999.

Naltrexone Pretreatment Decreases the Reinforcing Effectiveness of Ethanol and Saccharin but not PCP or Food in Rhesus Monkeys

Investigators at the University of Minnesota Medical School asked whether naltrexone's effect on reducing ethanol consumption results from selective changes in the reinforcing effectiveness of drug or non-drug reinforcers. Ethanol-maintained responding under progressive-ratio (PR) schedules was attenuated in a dose-dependent fashion by 0.3 and 1.0 mg/kg doses of naltrexone, and saccharin-maintained responding was also decreased at the 1.0 mg/kg dose. Additionally, after 5 days of naltrexone pretreatment, ethanol (8% w/v) - and saccharin-maintained responding immediately returned to or exceeded baseline levels, suggesting the development of tolerance. However, food- and PCP (0.25 mg/ml)-maintained responding and intake were not significantly affected by any of the naltrexone doses examined. This suggests that these reinforcers: 1) are not sensitive to naltrexone antagonism at the doses examined, 2) are mediated by non-opioid reinforcement mechanisms, and/or 3) have less intrinsic palatability. Rodefer, J.S., Campbell, U.C., Cosgrove, K.P., and Carroll, M.E. Psychopharmacology, 141, pp. 436-446, 1999.

Antinociceptive Effects of Cocaine in Rhesus Monkeys

Investigators at McLean Hospital/Harvard Medical School examined the antinociceptive effects of (-)cocaine, (+)cocaine, and cocaine methiodide alone and in combination with the mu-opioid agonist morphine in rhesus monkeys. Tail-withdrawal latencies from various warm water tail exposure durations (20-s maximum) were determined. (-)Cocaine (0.032-1.8 mg/kg, s.c.) produced dose-dependent antinociceptive effects and enhanced the antinociceptive effects of morphine. Neither (+)cocaine nor cocaine methiodide (0.1-10 mg/kg, s.c.) produced antinociception or altered the effects of morphine. Pretreatment with the serotonin receptor antagonist mianserin (0.1 - 4.32 mg/kg, intra-muscularly (i.m.)) produced dose-dependent rightward shifts in the dose-effect curve for (-)cocaine alone, and attenuated its induced enhancement of the antinociceptive effects of morphine. However, mianserin (0.32 mg/kg, i.m.) did not alter the antinociceptive effects of morphine alone. These results suggest that in rhesus monkeys, the effects of cocaine on nociception may be stereoselective and centrally mediated. These findings further suggest that the antinociceptive effects of cocaine in primates may be mediated at least in part by cocaine's effects on serotonergic systems. Gatch, M.B., Negus, S.S., Mello, N.K. Pharmacol. Biochem. Behav, 62, pp. 291-297, 1999.

Blocking Smoking Satisfaction With the Peripheral Nicotinic Antagonist Trimethaphan

Jed Rose and his colleagues at Duke University Medical Center investigated the role of peripheral nicotinic receptors in mediating the rewarding effects of cigarette smoking. Cigarette smokers rated cigarettes after intravenous infusion of the short-acting peripheral nicotinic receptor antagonist trimethaphan. Cigarette conditions included subjects' usual brand of cigarette, denicotinized tobacco cigarettes, and nicotine-injected cigarettes with the same tar delivery as denicotinized cigarettes but with an enhanced nicotine delivery equal to that of subjects' usual brands. (The latter cigarettes were rated as extremely harsh due to the high nicotine/tar ratio.) Compared with placebo, trimethaphan significantly attenuated the airway sensations associated with nicotine, and reduced satisfaction of the favored cigarette brand to the level of the other two cigarettes. These findings suggest that nicotinic receptors on peripheral nerve endings in the respiratory tract modulate smoking satisfaction and may be important in the maintenance of cigarette addiction. Rose, J.E., Westman, E.C., Behm, F.M., Johnson, M.P., Goldberg, J.S. Pharmacol Biochem Behav, 62, pp. 165-172, 1999.

Smoked Cocaine Self-Administration in Females and Voucher Incentives for Abstinence

Researchers at New York State Psychiatric Institute and the College of Physicians and Surgeons of Columbia University previously developed and reported on a laboratory model of "binge use" of cocaine that permitted characterization of behavior during the binge and during withdrawal from the binge. These researchers have now attempted to extend their model to a sample of high-use female cocaine abusers. Because of logistical difficulties associated with recruiting females for extended inpatient studies, the investigators used a modified protocol in which the withdrawal phase was conducted on an outpatient basis using a voucher procedure to facilitate abstinence so that withdrawal effects could be assessed. In the initial inpatient 4 to 5-day "binge" phase, ten non-treatment seeking females were permitted to smoke up to 6 doses of 50 mg cocaine base in two daily "binge" sessions for two consecutive days. Cocaine's subjective and cardiovascular effects were consistent with those previously reported in males, with the exceptions of a within-binge decrease in cocaine craving and a within-binge increase in tiredness among females. In the subsequent 2-week out-patient abstinent period, urine samples and questionnaire responses were collected daily and subjects received merchandise vouchers each time their urine sample contained less cocaine metabolite than the prior sample and was negative for all other drugs tested. During the outpatient withdrawal phase, although session attendance was excellent (98%), because only 56% of the urines indicated no new cocaine use, cocaine withdrawal effects could not be assessed. Nevertheless, achievement of 56% daily abstinence in a group of non-treatment seeking, high-use cocaine abusers serendipitously points to the utility of using voucher incentives in this population. Smoked Cocaine Self-Administration in Females and Voucher Incentives for Abstinence. Evans, S.M., Levin, F.R, Fischman, M.W., and Foltin, R.W. Journal of Substance Abuse, 10, pp. 143-162, 1998.

Male Rats Exhibit Greater Morphine Tolerance and Dependence Than Female Rats

Several rodent studies have shown that morphine's antinociceptive effect is greater for males than females. Dr. Rebecca Craft and colleagues have now reported sex differences in tolerance to morphine's antinociceptive effect. In the first experiment, whereas acute single doses of either 3.0, 5.6, or 10 mg/kg morphine produced significantly greater hotplate and tail withdrawal antinociception in males than females, delivery of all three doses spaced one week apart ("repeated dosing") did not produce sex differences; however, in males, morphine's antinociceptive effect was greater under acute dosing that under repeated dosing, whereas in females the effect was the same under the two procedures. In Experiment 2, in which morphine was delivered chronically twice daily, males exhibited significantly greater tolerance to morphine's antinociceptive effect than females and they exhibited greater recovery. During this experiment, 7 of 31 males, but none of the 29 females, died of respiratory depression. Morphine produced a decrease in the number of proestrus and estrus days and an increase in diestrus days. In Experiment 3, when morphine withdrawal was precipitated by naloxone, withdrawal scores were significantly greater for males than females with the greatest sex difference occurring in number of "wet-dog shakes." Craft, R.M., Stratmann, J.A., Bartok, T.I., and King, S.J. Psychopharmacology, 143, pp. 1-7, 1999.

Cue-Induced "Relapse" and "Priming" of Drug-Seeking Behavior: Dopaminergic Substrates in the Amygdala

The return of responding for drug during extinction, i.e. after terminating drug availability, has been suggested as a model of relapse. When the resurgence of responding is prompted by administering the previously self-administered drug, such as cocaine, this is known as "priming". Recent studies suggest that dopamine (DA) transmitter dynamics in the amygdala may play a role in incentive motivational processes that direct drug-seeking behavior during extinction. Dr. Janet Neisewander and colleagues at Arizona State University recently monitored extracellular DA in the amygdala during extinction and cocaine-priming. Different groups of rats were withdrawn for between one day and one month following two weeks of cocaine self-administration. Returning the animals to the self-administration chamber resulted in significant lever presses on the manipulandum that previously delivered cocaine. This drug-seeking behavior was accompanied by significant elevations of amygdaloid DA only in the one month withdrawal group. When i.p. cocaine was given to "prime" drug-seeking responses, rats under all withdrawal durations showed significant increases of DA overflow and also pressed the response lever that previously delivered drug infusions. However, animals from the one month withdrawal group had significantly greater increases in both the neurochemical and behavioral measures than did those in the other withdrawal conditions. These observations suggest that DA in the amygdaloid nuclei may be important in the neurochemical mechanisms underlying the "priming" effect. Furthermore, it appears that priming may be enhanced at more protracted post-withdrawal intervals. Tran-Nguyen, L.T.L., Fuchs, R.A., Coffey, G.P., Baker, D.A., O'Dell, L.E., and Neisewander, J.L. Neuropyschopharmacology, 19, pp. 48-59, 1999.

Motivational and Experiential Factors in the Development of Psychostimulant Tolerance

Dr. David Wolgin at Florida Atlantic University has been studying contingencies that modulate the development of tolerance to psychostimulants such as amphetamine. This approach emphasizes motivational and cognitive factors in drug-induced neuroadaptations that manifest as behavioral tolerance or sensitization. He has previously reported that animals will suppress stereotypical motor behaviors that interfere with the ingestion of a sweet milk solution and has proposed that tolerance to amphetamine's hypophagic effects can be attributed to this behavioral modulation. In a recent publication, he demonstrates that even animals with extremely high frequencies of amphetamine-induced stereotypy are capable of inhibiting this motor disruption and developing tolerance to amphetamine-induced hypophagia. In this study, Dr. Wolgin administered a chronic regimen of 5.0 mg/kg d-amphetamine to rats and observed enhanced stereotypical responding produced by this dose over the repeated administration. He then repeatedly administered 2.0 mg/kg d-amphetamine while animals consumed sweetened milk from a drinking spout. He found that the sensitized stereotypical responses did not interfere with the development of tolerance. This finding suggests that, given an appropriate incentive, rats can actively learn to suppress the expression of psychostimulant sensitization. If sensitization is an important process in the escalation of drug-seeking behavior, then the motivation to acquire non-drug rewards may contribute to the suppression of sensitization. Hughes, K.M., Popi, L., and Wolgin, D.L. Psychopharmacology, 140, pp. 445-449, 1999.

Abstinence Syndrome After Cessation from Smoked Marijuana in Humans

Precipitated withdrawal from delta9-tetrahydrocannabinol (THC), the major psychoactive component in marijuana, has been demonstrated in rats and there are clinical reports that abusers attempting to abstain from smoking marijuana experience a withdrawal syndrome. Investigators at the New York State Psychiatric Institute are the first to demonstrate physiological withdrawal symptoms accompanying the cessation of smoked marijuana in the laboratory. Twelve habitual marijuana smokers in a residential laboratory smoked marijuana cigarettes containing 1.8 or 3.1 percent THC. These investigators found, in comparison to placebo cigarettes, that ratings of anxiety were significantly increased during abstinence from 1.8 percent THC, and that ratings of stomach pain and irritability were increased during abstinence from 1.8 percent and 3.1 percent THC, respectively. There were also significant decreases in reports of being talkative, energetic and social during these abstinence periods as compared to baseline. Subjects were less accurate in tracking moving targets on a divided attention task following withdrawal. These data suggest that continued marijuana abuse may be driven by avoidance of negative abstinence symptoms, in addition to the direct reinforcing effects of the drug itself. Haney, M., Ward, A.S., Comer, S.D., Foltin, R.W., and Fischman, M.W. Psychopharmacology, 141, pp. 395-404, 1999.

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